scholarly journals Rho GTPases in the Amygdala—A Switch for Fears?

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1972
Author(s):  
Tasnuva Sarowar ◽  
Andreas M. Grabrucker
Keyword(s):  
Fear Conditioning ◽  
Rho Gtpases ◽  
Evolutionary Process ◽  
Molecular Switches ◽  
Normal Activity ◽  
Therapeutic Strategies ◽  
Fear Learning ◽  
Downstream Processes ◽  
Spine Morphogenesis

Fear is a fundamental evolutionary process for survival. However, excess or irrational fear hampers normal activity and leads to phobia. The amygdala is the primary brain region associated with fear learning and conditioning. There, Rho GTPases are molecular switches that act as signaling molecules for further downstream processes that modulate, among others, dendritic spine morphogenesis and thereby play a role in fear conditioning. The three main Rho GTPases—RhoA, Rac1, and Cdc42, together with their modulators, are known to be involved in many psychiatric disorders that affect the amygdala′s fear conditioning mechanism. Rich2, a RhoGAP mainly for Rac1 and Cdc42, has been studied extensively in such regard. Here, we will discuss these effectors, along with Rich2, as a molecular switch for fears, especially in the amygdala. Understanding the role of Rho GTPases in fear controlling could be beneficial for the development of therapeutic strategies targeting conditions with abnormal fear/anxiety-like behaviors.

scholarly journals Brief optogenetic inhibition of rat lateral or ventrolateral periaqueductal gray augments the acquisition of Pavlovian fear conditioning

2017 ◽  
Author(s):  
Neda Assareh ◽  
Elena E. Bagley ◽  
Pascal Carrive ◽  
Gavan P. McNally
Keyword(s):  
Fear Conditioning ◽  
Viral Vectors ◽  
Strong Support ◽  
Periaqueductal Gray ◽  
Fear Learning ◽  
Defensive Responses ◽  
Defensive Behaviors ◽  
The Relationship ◽  
Exact Timing

AbstractThe midbrain periaqueductal gray (PAG) coordinates the expression and topography of defensive behaviors to threat and also plays an important role in Pavlovian fear learning itself. Whereas the role of PAG in expression of defensive behavior is well understood, the relationship between activity of PAG neurons and fear learning, the exact timing of PAG contributions to learning during the conditioning trial, and the contributions of different PAG columns to fear learning are poorly understood. We assessed the effects of optogenetic inhibition of lateral (LPAG) and ventrolateral (VLPAG) PAG neurons on fear learning. Using adenoassociated viral vectors expressing halorhodopsin (eNpHR3.0), we show that brief optogenetic inhibition of LPAG or VLPAG during delivery of the shock unconditioned stimulus (US) augments acquisition of contextual or cued fear conditioning and we also show that this inhibition augments post-encounter defensive responses to a non-noxious threat. Taken together, these results show that LPAG and VLPAG serve a key role in regulation of Pavlovian fear learning at the time of US delivery. These findings provide strong support for existing models which state that LPAG and VLPAG contribute to a fear prediction error signal determining variations in the effectiveness of the aversive US in supporting learning.

scholarly journals Inhibition of the PI3 kinase cascade in corticolimbic circuit: temporal and differential effects on contextual fear and extinction

2013 ◽  
Vol 16 (4) ◽  
pp. 825-833 ◽  
Author(s):  
Milly Kritman ◽  
Mouna Maroun
Keyword(s):  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Fear Memory ◽  
Fear Learning ◽  
Contextual Fear ◽  
Pi3k Inhibition ◽  
Kinase Cascade ◽  
Differential Involvement ◽  
Phosphoinositide 3 Kinase

Abstract We studied the role of PI3K cascade in the basolateral amygdala (BLA) and the infralimbic region of the medial prefrontal cortex (IL-mPFC), in contextual fear learning and extinction in the rat. To that end, we micro-infused the phosphoinositide-3-kinase (PIK3) inhibitor LY294002 into either the mPFC or the BLA. Infusion of LY294002 into the BLA following fear conditioning was associated with enhanced freezing levels and impaired extinction in the subsequent sessions. Similarly, inhibition of PI3K in the BLA before the retrieval of fear memory was associated with impaired retrieval of the fear memory, which was expressed as reduced freezing levels that persisted over 2 d. In the IL-mPFC, only consolidation of fear extinction was impaired: micro-infusion of PI3K inhibitor following the retrieval of fear was associated with impaired extinction on the following days. These results indicate differences in the temporal parameters of the effects of PI3K inhibition in the IL-mPFC and in the BLA, which suggest differential involvement of these structures in long-term fear and in extinction of fear memory. Our findings provide additional evidence for the critical roles played by PI3K in intact formation of fear memory and in its extinction and add new evidence for a role of PI3K in consolidation of memory of extinction. Better understanding of the differential involvement of the PI3K cascade during acquisition and extinction of fear conditioning in the mPFC-amygdala circuit could potentially contribute to the understanding and treatment of anxiety disorders.

scholarly journals Independence of Cued and Contextual Components of Fear Conditioning is Gated by the Lateral Habenula

2020 ◽  
Author(s):  
Tomas E. Sachella ◽  
Marina R. Ihidoype ◽  
Christophe Proulx ◽  
Jorge H. Medina ◽  
Pablo Mendez ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Fear Conditioning ◽  
Neuronal Activity ◽  
Fear Memory ◽  
Fear Learning ◽  
Training Context ◽  
Lateral Habenula ◽  
Extreme Form ◽  
Pathological Conditions

AbstractFear is an extreme form of aversion that, if inappropriately generalized, initiates pathological conditions such as panic or anxiety disorders. Fear conditioning (FC) is the best understood model of fear learning. FC forms two associations that independently link the cue and the training context to fear responses. The lateral habenula (LHb) encodes aversive information. However, how the LHb participates in fear learning has not been intensively studied. Here we studied the role of the LHb in FC learning using optogenetics and pharmacological tools in rats. We found that disrupting neuronal activity of the LHb during training abolishes independent expression of contextual and cued memories, yet memory is normally expressed when the cue is played in the training context. Our results show that neuronal activity at the LHb regulates independent expression of sub-components of a fear memory, assigning to that structure a previously uncharacterized role as regulator of fear memories.

scholarly journals The role of GTPase-activating protein ARHGAP26 in human cancers

2021 ◽  
Author(s):  
Lingye Zhang ◽  
Anni Zhou ◽  
Shengtao Zhu ◽  
Li Min ◽  
Si Liu ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Molecular Mechanisms ◽  
Molecular Switches ◽  
Circular Rna ◽  
Biological Functions ◽  
Gtpase Activating Protein ◽  
Clinical Value ◽  
Rhoa Gtpase ◽  
Tumorigenesis And Progression

AbstractRho GTPases are molecular switches that play an important role in regulating the behavior of a variety of tumor cells. RhoA GTPase-activating protein 26 (ARHGAP26) is a GTPase-activating protein and inhibits the activity of Rho GTPases by promoting the hydrolytic ability of Rho GTPases. It also affects tumorigenesis and progression of various tumors through several methods, including formation of abnormal fusion genes and circular RNA. This review summarizes the biological functions and molecular mechanisms of ARHGAP26 in different tumors, proposes the potential clinical value of ARHGAP26 in cancer treatment, and discusses current issues that need to be addressed.

scholarly journals 4335 Role of PSD95 and nNOS interaction in gene regulation following fear conditioning and implications for molecular mechanisms underlying PTSD

2020 ◽  
Vol 4 (s1) ◽  
pp. 15-16
Author(s):  
Jheel Patel ◽  
Erik Dustrude ◽  
Melissa Haulcomb ◽  
Liangping Li ◽  
Guanglong Jiang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Fear Conditioning ◽  
Rna Sequencing ◽  
Basolateral Amygdala ◽  
Molecular Mechanisms ◽  
Conditioned Fear ◽  
Enrichment Analysis ◽  
Fear Learning ◽  
Post Traumatic Stress

OBJECTIVES/GOALS: Normal fear learning produces avoidance behavior that promotes survival, but excessive and persistent fear after trauma can lead to development of phobias and post-traumatic stress disorder (PTSD). Our goal is to understand the mechanism and identify novel genetic targets underlying fear responses. METHODS/STUDY POPULATION: Involvement of the amygdala in fear acquisition is well established and requires activation of N-methyl-D-aspartic acid receptors (NMDARs). At a cellular level, NMDAR activation leads to production of nitric oxide (NO) by a process mediated by interaction between postsynaptic density protein 95 (PSD95) and neuronal nitric oxide synthase (nNOS). To elucidate mechanisms underlying the role of the PSD95-nNOS-NO pathway in conditioned fear, here we use rodent behavioral paradigms, pharmacological treatment with a small molecular PSD95-nNOS inhibitor, co-immunoprecipitation, Western blotting, and RNA-sequencing. RESULTS/ANTICIPATED RESULTS: We show that fear conditioning enhances the PSD95-nNOS interaction and that the small-molecule ZL006 inhibits this interaction. Treatment with ZL006 also attenuates rodent cued-fear consolidation and prevents fear-mediated shifts in glutamatergic receptor and current densities in the basolateral amygdala (BLA). With RNA-sequencing, expression of 516 genes was altered in the BLA following fear expression; of these genes, 83 were restored by systemic ZL006 treatment. Network data and gene ontology enrichment analysis with Ingenuity Pathway Analysis and DAVID software found that cell-cell interaction, cognition-related pathways, and insulin-like growth factor binding were significantly altered. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results reveal novel genetic targets that underlie plasticity of fear-memory circuitry via their contribution of NMDAR-mediated fear consolidation and can inform future strategies for targeting fear related disorders like PTSD. CONFLICT OF INTEREST DESCRIPTION: Anantha Shekhar and Yvonne Lai are co-founders of Anagin, Inc., which is developing some of the related molecules for the treatment of PTSD.

Challenges of Fear Conditioning Research in the Age of RDoC

2017 ◽  
Vol 225 (3) ◽  
pp. 189-199 ◽  
Author(s):  
Tina B. Lonsdorf ◽  
Jan Richter
Keyword(s):  
Fear Conditioning ◽  
Clinical Diagnosis ◽  
Research Domain Criteria ◽  
Major Focus ◽  
The Future ◽  
Definition Of ◽  
Methodological Considerations ◽  
Research Domain

Abstract. As the criticism of the definition of the phenotype (i.e., clinical diagnosis) represents the major focus of the Research Domain Criteria (RDoC) initiative, it is somewhat surprising that discussions have not yet focused more on specific conceptual and procedural considerations of the suggested RDoC constructs, sub-constructs, and associated paradigms. We argue that we need more precise thinking as well as a conceptual and methodological discussion of RDoC domains and constructs, their interrelationships as well as their experimental operationalization and nomenclature. The present work is intended to start such a debate using fear conditioning as an example. Thereby, we aim to provide thought-provoking impulses on the role of fear conditioning in the age of RDoC as well as conceptual and methodological considerations and suggestions to guide RDoC-based fear conditioning research in the future.

Role of dorsal and ventral hippocampal muscarinic receptor activity in acquisition and retention of contextual fear conditioning.

2020 ◽  
Vol 134 (5) ◽  
pp. 460-470
Author(s):  
Claudia C. Pinizzotto ◽  
Nicholas A. Heroux ◽  
Colin J. Horgan ◽  
Mark E. Stanton
Keyword(s):  
Fear Conditioning ◽  
Muscarinic Receptor ◽  
Contextual Fear Conditioning ◽  
Receptor Activity ◽  
Contextual Fear

On the role of conflict in the evolutionary process

2016 ◽  
pp. 87-91
Author(s):  
V.I. Bol’shakov ◽  
◽  
Yu.I. Dubrov ◽  
Keyword(s):  
Evolutionary Process

Is Immune Response Relevant in Interstitial Lung Disease?

2020 ◽  
Vol 16 (1) ◽  
pp. 18-27
Author(s):  
Manzoor M. Khan
Keyword(s):  
Immune Response ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Lung Fibrosis ◽  
Lymphocytic Infiltration ◽  
Therapeutic Strategies ◽  
Mediators Of Inflammation ◽  
Acquired Immune Responses ◽  
Novel Therapeutic Strategies

Interstitial lung disease, a term for a group of disorders, causes lung fibrosis, is mostly refractory to treatments and has a high death rate. After diagnosis the survival is up to 3 years but in some cases the patients live much longer. It involves a heterogenous group of lung diseases that exhibit progressive and irreversible destruction of the lung due to the formation of scars. This results in lung malfunction, disruption of gas exchange, and eventual death because of respiratory failure. The etiology of lung fibrosis is mostly unknown with a few exceptions. The major characteristics of the disease are comprised of injury of epithelial type II cells, increased apoptosis, chronic inflammation, monocytic and lymphocytic infiltration, accumulation of myofibroblasts, and inability to repair damaged tissue properly. These events result in abnormal collagen deposition and scarring. The inflammation process is mild, and the disease is primarily fibrotic driven. Immunosuppressants do not treat the disease but the evidence is evolving that both innate and acquired immune responses a well as the cytokines contribute to at least early progression of the disease. Furthermore, mediators of inflammation including cytokines are involved throughout the process of lung fibrosis. The diverse clinical outcome of the disease is due to different pattern of inflammatory markers. Nonetheless, the development of novel therapeutic strategies requires better understanding of the role of the immune response. This review highlights the role of the immune response in interstitial lung disease and considers the therapeutic strategies based on these observations. For this review several literature data sources were used to assess the role of the immune response in interstitial lung disease and to evaluate the possible therapeutic strategies for the disease.

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